Vitamin D Levels in Patients with Colorectal Cancer and Matched Household Members.

Background
Vitamin D levels, as measured by 25-hydroxyvitamin-D [25(OH) D], are inversely related to the risk of developing colorectal cancer (CRC). Given shared demographic and lifestyle factors among members of the same household, we sought to examine vitamin D levels and associated lifestyle factors in household members of CRC patients.


Methods
Thirty patients with pathologically confirmed CRC were enrolled prior to oncologic therapy along with unrelated household members who were matched for age (+/- 5 years) and race. In addition to serum blood draws for 25(OH)D levels at baseline and six-month follow-up, questionnaires collected gender, vitamin use, body mass index, family history of CRC, race, dietary vitamin D, UV exposure, and exercise.


Results
Median serum 25(OH) D levels were 26.8 ng/mL for CRC patients versus 27.3 for household members (P=0.89). Vitamin-D associated factors such as dietary vitamin D intake, UV exposure, gender, multivitamin use, vitamin D supplement use, and family history of CRC were not significantly different between CRC patients and paired household members (P>0.05). Household members were more likely than CRC patients to be overweight and to exercise more.


Conclusions
Vitamin D levels and many associated lifestyle factors were not significantly different between CRC patients and unrelated paired household members. Given comparable vitamin D levels, further investigation into whether age-matched household members of CRC patients may be at increased risk for CRC is warranted.


Background
Epidemiological data have substantiated that 25-hydroxyvitamin-D [25(OH)D], the physiologically active metabolite of vitamin D, is inversely related to the risk of developing colorectal cancer (CRC) [1]. Age, race, ultraviolet (UV) light exposure, dietary vitamin D consumption, vitamin D supplement use, body mass index (BMI), and blood draw season are associated with 25(OH)D levels [2]. A growing body of epidemiologic data suggests that lifestyle factors such as diet and exercise also play a role in the development of CRC [3].
In this study, we aimed to evaluate risk for vitamin D deficiency in patients with a new diagnosis of CRC and in matched household members. Our hypothesis was that patients and their household members would share common lifestyle factors associated with vitamin D status such as BMI, UV exposure, and physical activity.

Methods
We recruited patients who were evaluated at our institution for a new diagnosis of pathologically confirmed CRC of any stage and prior to initiation of any oncologic therapy. For patients with early stage disease who underwent surgical resection of the primary tumor, patients were enrolled within eight weeks following surgical resection.
This study was approved by the UCSF Committee for Human Research (IRB Number 10-03402), and all participants provided informed consent. Measurement of 25(OH)D by clinical providers and vitamin D repletion and/or supplementation, according to individual care practices, were not restricted during the study period. A detailed description of subject enrollment, questionnaire development, and assay methodology was published previously [4].
The study was embedded in a larger study of vitamin D levels in CRC patients [4], and household members were recruited by convenience sampling for a subset of patients. Household members were invited to participate and were matched for age (±5 years) and race. Prior data have shown that with cancer patients, family or friend controls typically do not differ from matched neighborhood controls in age, BMI, tobacco use, and alcohol use [5].
CRC patients and their respective household member completed study visits on the same dates to control for seasonal variation of serum 25(OH)D levels. A baseline questionnaire administered to all participants collected gender, vitamin use, BMI, family history of CRC, race, dietary vitamin D, UV exposure, and exercise. Colon or rectal cancer in a parent or sibling was considered a family history of CRC. The dietary vitamin D questionnaire solicited consumption frequency of 13 common foods with high vitamin D contributions (milk, soy milk, yogurt, cheese, fortified orange juice, canned tuna fish, sardines, shellfish, dark meat fish, other fish, eggs, beef liver, and cold breakfast cereal) [6]. A physical activity score was calculated by self-reported frequency of performing nine common exercise activities, yielding units of activity-specific MET-hours per week. Phlebotomy samples for serum 25(OH)D assay evaluation were collected at the time of study registration and at sixmonth follow-up.
To compare questionnaire responses and serum 25(OH)D levels between CRC patients and household members, a likelihood ratio test fitted to a conditional logistic regression model was used for each variable. The analysis was done using SAS statistical software. Doublesided p-values <0.05 were considered statistically significant.

Discussion
Serum 25(OH)D levels were comparable between CRC patients and household members at both baseline and six-month timepoints. Similarly, a number of lifestyle factors known to be associated with vitamin D status, including relative UV exposure and dietary vitamin D consumption, were similar between CRC patients and matched household members. Using the widely accepted vitamin D sufficiency threshold of serum 25(OH)D greater than 30 ng/mL [7,8], most participants in both groups were vitamin D insufficient or deficient. However, it has been proposed by the Institute of Medicine that the lower limit of sufficiency should be 20 ng/mL [9], which is below median serum 25(OH)D in both CRC patients and household pairs.
We did observe differences in BMI and exercise between CRC patients and unrelated household members. However, it is possible that the variables which differed, BMI and exercise, were biased by the clinical scenario following a CRC diagnosis. In consideration of the fact that 60% of CRC patients underwent tumor resection within eight weeks prior to administration of the baseline questionnaire, differences in exercise patterns amongst CRC patients versus household members were likely influenced by temporary exercise restrictions imposed during recovery from surgery. Lower BMI among CRC patients versus household members may reflect that weight loss is a common presenting symptom in patients with CRC [10].
We found that household members did not have significantly different serum 25(OH)D levels from CRC patients at baseline or six-months after treatment. Pairs were unrelated; therefore, these data likely reflect shared lifestyle factors rather than shared genetic contributions to vitamin D metabolism. CRC patients and partners were found to have numerous similarities in lifestyle factors that are known to be associated with increased risk for CRC. In light of these similarities in lifestyle, further investigation into whether unrelated household members may be at increased risk for CRC is warranted.  Summary of clinicodemographic factors.